Aberrant O-glycosylation inhibits stable expression of dysadherin, a carcinoma-associated antigen, and facilities cell-cell adhesion

Hitomi Tsuji, Seiichi Takasaki, Michiie Sakamoto, Tatsuro Irimura, Setsuo Hirohashi

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48 Citations (Scopus)

Abstract

Recently, we identified dysadherin, a novel carcinoma-associated glycoprotein, and showed that overexpression of dysadherin in human hepatocarcinoma, PLC/PRF/5 cells could suppress E-cadherin-mediated cell-cell adhesion and promote tumor metastasis. The present study shows evidence that dysadherin is actually O-glycosylated. This was based on a direct carbohydrate composition analysis of a chimera protein of an extracellular domain of dysadherin fused to an Fc fragment of immunoglobulin. To assess the importance of O-glycosylation in dysadherin function, dysadherin-transfected hepatocarcinoma cells were cultured in a medium containing benzyl-α-GalNAc, a modulator of O-glycosylation. This treatment facilitated homotypic cell adhesion among dysadherin transfectants accompanied with morphological changes, indicating that the anti-adhesive effect of dysadherin was weakened. Modification of O-glycan synthesis also resulted in down-regulation of dysadherin expression and up-regulation of E-cadherin expression in dysadherin transfectants but did not affect E-cadherin expression in mock transfectants. Structural analysis of O-glycans released from the dysadherin chimera proteins indicated that a series of O-glycans with core 1 and 2 structures are attached to dysadherin, and their sialylation is remarkably inhibited by benzyl-α-GalNAc treatment. However, sialidase treatment of the cells did not affect calcium-dependent cell aggregation, which excluded the possibility that sialic acid itself is directly involved in cell-cell adhesion. We suggest that aberrant O-glycosylation in carcinoma cells inhibits stable expression of dysadherin and leads to the up-regulation of E-cadherin expression by an unknown mechanism, resulting in increased cell-cell adhesion. The carbohydrate-directed approach to the regulation of dysadherin expression might be a new strategy for cancer therapy.

Original languageEnglish
Pages (from-to)521-527
Number of pages7
JournalGlycobiology
Volume13
Issue number7
DOIs
Publication statusPublished - 2003 Jul 1

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Keywords

  • Benzyl-α-Ga1NAc
  • Cell-cell adhesion
  • Dysadherin
  • E-cadherin
  • O-glycosylation

ASJC Scopus subject areas

  • Biochemistry

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